Disrupting metformin adaptation of liver cancer cells by targeting the TOMM34/ATP5B axis
Abstract Metformin, a well‐known antidiabetic drug, has been repurposed for cancer treatment; however, recently observed drug resistance and tumor metastasis have questioned its further application. Here, we found that long‐term metformin exposure led to metabolic adaptation of hepatocellular carcin...
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| Format: | Article |
| Language: | English |
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Springer Nature
2022-11-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202216082 |
| _version_ | 1827045099812421632 |
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| author | Ping Jin Jingwen Jiang Li Zhou Zhao Huang Siyuan Qin Hai‐Ning Chen Liyuan Peng Zhe Zhang Bowen Li Maochao Luo Tingting Zhang Hui Ming Ning Ding Lei Li Na Xie Wei Gao Wei Zhang Edouard C Nice Yuquan Wei Canhua Huang |
| author_facet | Ping Jin Jingwen Jiang Li Zhou Zhao Huang Siyuan Qin Hai‐Ning Chen Liyuan Peng Zhe Zhang Bowen Li Maochao Luo Tingting Zhang Hui Ming Ning Ding Lei Li Na Xie Wei Gao Wei Zhang Edouard C Nice Yuquan Wei Canhua Huang |
| author_sort | Ping Jin |
| collection | DOAJ |
| description | Abstract Metformin, a well‐known antidiabetic drug, has been repurposed for cancer treatment; however, recently observed drug resistance and tumor metastasis have questioned its further application. Here, we found that long‐term metformin exposure led to metabolic adaptation of hepatocellular carcinoma (HCC) cells, which was characterized by an obvious epithelial–mesenchymal transition (EMT) phenotype and compensatory elevation of oxidative phosphorylation (OXPHOS). TOMM34, a translocase of the outer mitochondrial membrane, was upregulated to promote tumor metastasis in response to metformin‐induced metabolic stress. Mechanistically, TOMM34 interacted with ATP5B to preserve F1FO‐ATPase activity, which conferred mitochondrial OXPHOS and ATP production. This metabolic preference for OXPHOS suggested a large requirement of energy supply by cancer cells to survive and spread in response to therapeutic stress. Notably, disturbing the interaction between TOMM34 and ATP5B using Gboxin, a specific OXPHOS inhibitor, increased sensitivity to metformin and suppressed tumor progression both in vitro and in vivo. Overall, this study demonstrates a molecular link of the TOMM34/ATP5B‐ATP synthesis axis during metformin adaptation and provides promising therapeutic targets for metformin sensitization in cancer treatment. |
| first_indexed | 2024-03-07T18:08:18Z |
| format | Article |
| id | doaj.art-21de7353346a45f899760eb85b44cfa8 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2025-02-18T14:19:31Z |
| publishDate | 2022-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-21de7353346a45f899760eb85b44cfa82024-10-28T08:51:56ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-11-01141211910.15252/emmm.202216082Disrupting metformin adaptation of liver cancer cells by targeting the TOMM34/ATP5B axisPing Jin0Jingwen Jiang1Li Zhou2Zhao Huang3Siyuan Qin4Hai‐Ning Chen5Liyuan Peng6Zhe Zhang7Bowen Li8Maochao Luo9Tingting Zhang10Hui Ming11Ning Ding12Lei Li13Na Xie14Wei Gao15Wei Zhang16Edouard C Nice17Yuquan Wei18Canhua Huang19State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan UniversityColorectal Cancer Center, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan UniversityWest China School of Basic Medical Sciences & Forensic Medicine, Sichuan UniversitySchool of Basic Medical Sciences, Chengdu University of Traditional Chinese MedicineSchool of Basic Medical Sciences, Chengdu University of Traditional Chinese MedicineWest China School of Basic Medical Sciences & Forensic Medicine, Sichuan UniversityClinical Genetics Laboratory, Affiliated Hospital & Clinical Medical College of Chengdu UniversityMental Health Center and Psychiatric Laboratory, The State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityDepartment of Biochemistry and Molecular Biology, Monash UniversityState Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan UniversityAbstract Metformin, a well‐known antidiabetic drug, has been repurposed for cancer treatment; however, recently observed drug resistance and tumor metastasis have questioned its further application. Here, we found that long‐term metformin exposure led to metabolic adaptation of hepatocellular carcinoma (HCC) cells, which was characterized by an obvious epithelial–mesenchymal transition (EMT) phenotype and compensatory elevation of oxidative phosphorylation (OXPHOS). TOMM34, a translocase of the outer mitochondrial membrane, was upregulated to promote tumor metastasis in response to metformin‐induced metabolic stress. Mechanistically, TOMM34 interacted with ATP5B to preserve F1FO‐ATPase activity, which conferred mitochondrial OXPHOS and ATP production. This metabolic preference for OXPHOS suggested a large requirement of energy supply by cancer cells to survive and spread in response to therapeutic stress. Notably, disturbing the interaction between TOMM34 and ATP5B using Gboxin, a specific OXPHOS inhibitor, increased sensitivity to metformin and suppressed tumor progression both in vitro and in vivo. Overall, this study demonstrates a molecular link of the TOMM34/ATP5B‐ATP synthesis axis during metformin adaptation and provides promising therapeutic targets for metformin sensitization in cancer treatment.https://doi.org/10.15252/emmm.202216082hepatocellular carcinomametastasismetformin adaptationoxidative phosphorylationTOMM34 |
| spellingShingle | Ping Jin Jingwen Jiang Li Zhou Zhao Huang Siyuan Qin Hai‐Ning Chen Liyuan Peng Zhe Zhang Bowen Li Maochao Luo Tingting Zhang Hui Ming Ning Ding Lei Li Na Xie Wei Gao Wei Zhang Edouard C Nice Yuquan Wei Canhua Huang Disrupting metformin adaptation of liver cancer cells by targeting the TOMM34/ATP5B axis EMBO Molecular Medicine hepatocellular carcinoma metastasis metformin adaptation oxidative phosphorylation TOMM34 |
| title | Disrupting metformin adaptation of liver cancer cells by targeting the TOMM34/ATP5B axis |
| title_full | Disrupting metformin adaptation of liver cancer cells by targeting the TOMM34/ATP5B axis |
| title_fullStr | Disrupting metformin adaptation of liver cancer cells by targeting the TOMM34/ATP5B axis |
| title_full_unstemmed | Disrupting metformin adaptation of liver cancer cells by targeting the TOMM34/ATP5B axis |
| title_short | Disrupting metformin adaptation of liver cancer cells by targeting the TOMM34/ATP5B axis |
| title_sort | disrupting metformin adaptation of liver cancer cells by targeting the tomm34 atp5b axis |
| topic | hepatocellular carcinoma metastasis metformin adaptation oxidative phosphorylation TOMM34 |
| url | https://doi.org/10.15252/emmm.202216082 |
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